The design of novel anticancer agents is one of the most active fields in Medicinal Chemistry, as the number of effective drugs for treatment of cancer is still very limited. This demand for new... Show moreThe design of novel anticancer agents is one of the most active fields in Medicinal Chemistry, as the number of effective drugs for treatment of cancer is still very limited. This demand for new drugs is even higher, considering the high cancer-prevalence rate in our society. The therapeutic application of metal complexes is an under-developed area of research and basic principles in the development of metallopharmaceuticals are lacking, or at least just recently being discovered. Metal-containing agents may offer unique therapeutic opportunities. However, significant obstacles, including potential metal accumulations and toxicities, require further research before a promising metal compound may be introduced in the clinic. In particular several ruthenium and gold coordination compounds have shown promising application as anticancer agents. In these terms, this thesis project, performed in the Coordination and Bioinorganic Chemistry group in the Leiden Institute of Chemistry, comprises the design, synthesis, detailed characterization (i.e. elemental analysis, UV-Vis spectroscopy, IR, far-IR, NMR, mass spectroscopy and X-ray single-crystal structure determination) and also the biological evaluation of novel gold compounds and ruthenium compounds. The promising cytotoxic activity developed for several of these compounds and the findings from this research are providing a better understanding of chemistry of Ru(III) and Ru(II) and Au(III) coordination compounds and their structure-activity relationships and may lead to the development of improved ruthenium and gold-chemotherapeutic drugs. Show less
The perfect anticancer drug would kill cancer cells without causing any harm to the surrounding healthy tissues. That ideal medicine is searched for in this thesis, in the form of a ruthenium... Show moreThe perfect anticancer drug would kill cancer cells without causing any harm to the surrounding healthy tissues. That ideal medicine is searched for in this thesis, in the form of a ruthenium coordination complex.Metal complexes are known to interact with DNA in several different modes, amongst which are coordination, intercalation of the aromatic part of the molecule between the DNA base-pairs and binding of the complex to one of the DNA grooves.Is there a correlation between the ruthenium–DNA interactions and the cytotoxicity of these complexes? Three ruthenium polypyridyl complexes (1a-c) were synthesized and characterized, which can coordinate to guanine. The structure-related 1e and 1f, as well as the dinuclear complex 1g, were also chosen for these studies. The interactions between each ruthenium complex and DNA were studied; the activities of the compounds in different cancer cells were tested.The results of these tests suggest that 1a-c and 1e coordinate to DNA, while 1g probably fits in the DNA groove. These complexes display moderate activity in some cancer cell lines. The inactive complex 1f can coordinate to guanine and bind to DNA via intercalation or groove-binding. 1f is the only one of the studied compounds that lacks an azo group, which suggests that this group is essential for cytotoxicity.The interactions between metal complexes and other biological molecules are also mentioned. Show less
